Alzheimer disease (AD) is caused by heterogeneous genetic and probably environmental factors. Although the etiology of the disease is still not clear, several lines of evidence indicate that the integrity and number of cellular organelles that sustain neuronal vesicular axoplasmic transport, including endoplasmic reticulum (ER), Golgi, endosomes, and large dense core vesicles (LCDCVs) are compromised in AD. These observation suggest those factors that compromise that comprise neuronal vesicular transport may also be causally involved in the development of AD. This hypothesis, while does not disregard the pathological significance and consequence of neurofibrillary tangles (NFTs) and neuritic plaques (NPs), it emphasizes the need to search for abnormalities in neuronal protein transport upstream of the formation of NFTs and NPs. The association of the Alzheimer's amyloid precursor protein (APP) with the cytoskeleton and its axoplasmic transport raise the possibility that familial AD (FAD)-linked APP mutations alter the function and vesicular transport of APP. Presenilin l (PSl) is an integral membrane protein of unknown function. It is cleaved post-translationally to yield an N-terminal fragment and a C-terminal fragment. Many PSl mutants have been linked to the development of FAD. We obtained preliminary data that PSl proteolytic fragments are expressed in LDCVs, chromaffin granules (CGs), and somatodendritic clathrin coated vesicles (SDCCVs) suggesting that this protein play a role in vesicular function. This observation raises the possibility that the FAD PSl mutations may interfere with the function of these vesicles. The purpose of this proposal is to further examine the vesicular localization of PSl and its proteolytic fragments, to test the hypothesis that PSl has a vesicular function and to examine the effects of FAD-linked PSl mutations on vesicular transport. The results of our research should further out understanding of the mechanisms involved in the neuropathology of AD.